Substituted dihydroisoindoles

ABSTRACT

Substituted dihydroisoindoles e.g., 1-( Alpha -hydroxy-pchlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole are prepared from corresponding 1-(substituted phenacyl)-1(substituted phenyl)-3-ethoxy-1H-isoindole, and are useful in the treatment of lipidemia.

United States Patent Eberle July 1, 1975 SUBSTITUTED DIHYDROISOINDOLES[52] US. Cl. 260/326.1; 260/325; 424/274 M ,N [51] Int- Cl. C07d 27/00;C07d 27/48 [75] Invent K hem J 58 Field of Search 260/325, 326.1;424/274 [73] Assignee: Sandoz, lnc., Hanover, NJ.

. Primar ExaminerElbert L. Roberts 22 F] d: l 9, 1973 y 1 I e Ju yAttorney, Agent, or Firm-Gerald D. Sharkin; Robert PP N04 377,642 S.Honor; Thomas O. McGovern Related US. Application Data [63]Continuation-impart of Ser. No. 323,629, Jan. 15, [57] ABSTRACT 1973,abandoned, which is a continuation-in-part of Ser. No. 301,660, Oct. 27,1972, abandoned, which is a continuation-in-part of Ser. No. 240,277,March 31, 1972, abandoned, which is a continuation-in-part of Ser. No.220,494, Jan. 24, 1972, abandoned, which is a continuation-in-part ofSer. No. 170,332, Aug. 9, 1971, abandoned.

Substituted dihydroisoindoles e.g., l-(a-hydroxy-pchlorophenethyl l-(p-chlorophenyl )-2,3- dihydroisoindole are prepared from corresponding1- (substituted phenacyl)-l-(substituted phenyl)-3-ethoxy-ll-l-isoindole, and are useful in the treatment of lipidemia.

35 Claims, No Drawings 1 2 SUBSTITUTED DIHYDROISOINDOLES mers. Racemicand diastereoisomeric mixtures of the compound of formula (I) may beseparated into indi- This application is a continuation-in-part ofcopendid i s b v ntional techniques, ing U.S. Patent application Ser.No. 323,629, filed Jan. The compounds of the formula I are obtainable by15, 1973, now abandoned. which in turn is a continuathe followingreaction scheme:

R R2 R3 }2 R3 3 2 CH X CH (1H IN M! 03 Z \A (LI) R (I) tioninpart ofcopending U.S. Patent application Ser. wherein No. 301,66O,f1led Oct.27, 1972 now abandoned which R,, R R R and the proviso are as previouslydein turn in a continuation-in-part ofU.S. Patent applicafined; and tionSer. No. 240,277, filed Mar. 31, l972 now aban- X is -CHOH or CO-; donedwhich in turn is a continuation-in-part of U.S. Z is CO or Patentapplication Serv No. 220,494, filed Jan. 24, i 1972 now abandoned, whichin turn is a continuationin-part of U.S. Patent application Ser. No.170,332, filed Aug. 9, 1971. now abandoned. B

This invention relates to substituted dihydroisoindoles and to theirpreparation. In particular, the appliand cation relates tol-(a-hydroxy-substituted phenethyl)- A is hy rog n'when Z is CO- or Vl-(substituted phenyl)-2,3-dihydroisoindoles, their AB togetherrepresent a second carbon to nitrogen pharmaceutically acceptable acidaddition salts, inter ond when Z is mediates used in their preparationand to their use as hypocholesterolemic agents.

The compounds of this invention may be represented 2 5' by the followingformula: B

reducing a compound of the formula (II) with diborane R2 R (I) in asuitable inert organic solvent. Although the partic- 3 40 ular solventused is not critical, hydrogen solvents, e.g.,

benzene, toluene, xylene and the ethers such as die- CH H thylether,tetrahydrofuran and dioxane are preferred,

M i h especially tetrahydrofuran. The production of compounds (I) may becarried out at a temperature of from about 0 to 80C, preferably 20 to30C. The reaction time may vary widely and is usually in the range offrom 1 to 48 hours. The reaction can be carried out in an inertatmosphere such as helium, argon, or nitrogen. Recovery of the compoundsof formula (I) may be af- 50 fected using conventional techniques, e.g.,filtration,

where R and R each independently represent hydrogen or halo having anatomic weight of 19 to 36 and R and R each independently representshydrogen; lower alkyl having 1 to 4 carbon atoms, e.g., TZLILZZZSQZZ'iiilirlfl lilii if??? if recrystalhzamni p p y The compounds of theformula (II) in which X is and the like; halo having an atomic weight of19 to CO- and Z IS 36 or trifluoromethyl;

provided that when both R and R are trifluoromethyl "y H they are not onadjacent carbon atoms, or pharmaceu- 25 tically acceptable acid additionsalts thereof.

The compounds of formu a P0 IWO symme is the preferred starting materialand may be prepared ric carbon atoms and therefore exist as four opticalisoby the following procedure:

Vii H M N N (III) f (IIIa.) OC l-i The compounds of the formula (I) areprepared by Continued GH -C Y-CH fi (Iv) q Rh where metal reducing agentpreferably an alkali metal boro- MH is an alkali metal hydride hydridereducing agent in an inert solvent. The particu- Y is halo having anatomic Weight of 35 80 and lar alkali metal reducing agent used is notcritical al R4 and the provlso are as Previously though sodiumborohydride is the preferred reducing finedagent. The particular solventused will depend on the The Compounds of formula (Ha) are Prepared by 20reducing agent used and include lower alkanols, hydrotreating a compoundofformula (Ill) first with an alkali carbons, Such as benzene, tolueneand Xylene, and mflal hydride and then with a Substituted phenzlcylha'ethers, such as diethyl ether, tetrahydrofuran and dioxlide in asuitable inert organic solvent. The alkali metal ane with theborohydrides and with the alkali metal hyfiride is preferably sPdlumhydride or Potasslum drides, all of the foregoing excluding thealkanols. The dride. The particular inert solvent used is not criticalprocess is Suitable effected ata temperature of from butdimethylformamide is particularly preferred. The 7 o to 80C preferably oto for the more temperature is not critical, but the process ispreferably five alkali metal hydrides and to for the alkali came? out atemoperature of i about 0 80 metal borohydrides. The reaction time isnot critical fispeciany 20 to 30 The can gamed out and may for examplevary from 1 to 5 hours. The reacm an inert atmosphere such as previouslyindicated and 30 tion is preferably Carried out in an inert atmospherethe time may vary widely and is usually in the range of such as nitrogenargon or heliurm l to 24 hours. Recovery f the produc y The process forpreparing the compounds of formula fected usmg conventional techmquesfiltratlon (llb) yields two racemic isomers, both of which containrecrystallization two enantiomers. The racemic isomers are readily sep-The Compounds of formula (H) m Yvhlch arated from each other byconventional techniques, CHOH- may be prepared by the following reactionchromatotraphy scheme: The compounds of formula (II) in which Z is -CO Rand A is hydrogen can be prepared in accordance with l 40 the followingscheme:

CH2C R3 0 R o h A H+ (IIc) R. where [MH] is an alkali metal reducingagent and A, Z, R R R R and the proviso are as previously 5 defined.where The compounds of formula (llb) are prepared by X, R R R R d hproviso are as defined treating a compound of formula with an alkaliabove.

The compounds of formula (lld) are prepared by hydrolyzing a compound ofthe formula (lle) in an inert solvent under acidic conditions. i.e., ata pH value of less than 3 and preferably from 1 to 2. Although the 6ylene chloride, conveniently at a temperature of from about to C forabout 2-16 hours.

The pharmaceutically active isomers of the compounds of formula (I) inresolved form may conveparticular acid used to provide the acidicconditions is 5 niently be prepared by the following reaction scheme:

by treatment with triethyloxonium tetrafluoroborate in a solvent such aschlorinated hydrocarbons, e.g.. meth- Separation where h R2! R3! R41above,

The asterisks indicate that the isomer is present in essentially chiralform, i.e., in about percent by weight or greater optically pure form.

The reduction of the compound of formula (Ilf) is carried out in thesame manner as the reduction of compound above and leads to a mixture oftwo isomers, the nature of which will depend on the initial isomer'ofthe compound (IIf) The resulting isomeric mixture (Hg) is separated intoindividual isomers (lIg') in the second stage of the process, employingconventional techniques, e.g. column chromatography.

In the final stage ofthe process, the separated isomer of formula (llg)is reduced with diborane in an inert organic solvent in the same manneras the reduction of the compounds of formula (ll) above is carried out.

The resulting products may be isolated and purified using conventionaltechniques. The above process is particularly useful in preparing thecompounds of formula (I) in which R is in the para position.

The compounds of formula (Hf) may be produced in accordance with thefollowing reaction scheme:

and the proviso are as defined i R1: Rh

052cc rz'leael uI'aItS Catalyst (vI) (VII) where The present inventionalso encompasses the levo and dextro acid halides of formula (VI) whichare prepared Y halo havmg an atomlc Welght of about to 80 15 byhalogenating the respective levo or dextro acid and . (VIII) with anmorganlc acid hallde, e.g., SOCI PCl R4 and the Prom" are as Set above"or SOBr- The reaction is illustrated in the following The compounds offormula (IIf) are prepared by scheme using a thionyl halide, thepreferred halogenattreating the corresponding isomer of formula (VI)with ing agent.

(VIII) (VI) :1 Compound of formula (VII) in a solvent and in the wherepresence ofa Friedel Crafts catalyst. The particular sol- 3g Y, R and Rare as set out above. vent used in the reaction is not critical; buthalogenated The reaction is carried out in excess halogenating alkanessuch as methylene dichloride, ethylene dichloagent or inert solvent. Thepreferred inert solvents are ride and the like, alkane such as hexane orheptane, benzene, toluene, pentane, hexane, heptane, methylethers suchas diethyl ether, tetrahydrofuran and the ene dichloride, chloroform andthe like, especially eth' like are preferred, and excess reactant offormula (VII) 40 ylene dichloride. Although the time and temperature ofis especially preferred. The Friedel Crafts catalyst used the reactionare not Critical, it is preferred that the recan be any of theconventional Friedel Crafts catalysts, action be run for approximately30 minutes to 24 hours for example, ferric chloride, stannic chloride,boron triat a temperature between about 30C. and 125C, and fluoride,zinc chloride and especially aluminum trichloespecially at the refluxtemperature of the system. It is ride. Although the temperature of thereaction iS not also preferred that an N,N-di lower alkyl aliphatic acidcritical, it is preferred that the reaction be run at temamide, such asdimethyl acetamide or dimethylformperatures between about -70 to 100C,preferably be amide be added to the reaction mixture to facilitate thetween to 30C and more especially between 50 reaction. One of the aboveinert atmospheres may also to 0. The reaction can be carried out aninert atmobe used. The acid halide may be recovere'd by conven spheresuch as already indicated and the reaction 50 tional techniques, e.g.,evaporation or distillation. should be run for from about 30 minutes to20 hours. The racemic formtof compound (VI) can be pre- The product isseparated by conventional techniques, pared by the above procedure usingcompound (Vllla) Chromatography I below, the racemic form of compound(VIII).

It will be appreciated that compound (He) in which The Compounds offormula (VIII) are novel and are Z is CO- and A is hydrogen can beprepared by the included within the scope of this invention, and may beabove process by using the racemic form of compound prepared inaccordance with the following reaction (VI). scheme:

B01; Resolution [H20] II (VIIIa) (VIIIb) he e of the compounds (IX) maybe effected using conven- BOH is an optically active base and tionaltechniques eg. evaporation, extraction, etc. R and R are as definedabove. The hydrolysis of the ester (IX) to the acid (Villa) Thecompounds of formula (VIII) are prepared by is carried out using an acidor base hydrolyzing agent resolution and decomposing of thediastereoisomeric 5 i n eous solvent. The acidic hydrolyzing agentssalts IIIb) formed y treilting t e omp n of O are the same as those usedabove in the decomposition mula (Villa) with an optically active base inan inert of compound (VIIIb) and the basic hydrolyzing agent solvent.The optically active base can be any of the can be any of the standardbasic hydrolyzing agents standard basic resolving agents, such ascinchonine cinpreferably potassium hydroxide or sodium hydroxide.Chonidine, quinine. rychnine. morphin d t e like, The aqueous solventcan be water or water plus a water especi lly brucinethe Solvent usedcan be inert miscible organic solvent such as the lower alcoholshavsolvent. preferably lower alkanols such as methanol, i l to 4 c rbonatoms especially methanol, ethanol ethanol. etc. acetone,tetrahydrofuran and the like. esand the like. Although the temperatureis not critical, pecially methanol. Although the temperature of the reit is preferred that the reaction be carried out at a temaction is notcritical it is preferred that the reaction be perature of from 20 tol50, especially between 50 to carried out at from about to 150C.preferably 80. The acid (VIIla) is recovered by conventional to 30C. Thetime ofthe reaction is not critical and can techniques, for example,evaporation or precipitation. range from few minutes to several hours.The diastere- Many of the compounds of formulas (IV), (V) and oisomers(VIIIb) are resolved by conventional tech- (VII) are known and arereadily prepared according to niques, e.g., fractional crystallization.methods disclosed in the literature. Compounds of for- I Thedecomposition of compound (VIIIb) to the optimulas (IV), (V) and (VII)which are not specifically cally active acid (VIII) is carried out bytreating the isodi lo ed may be prepared by methods analogous to lateddiflstefeoiwmer 0f fQfmula with an acid those in the literature fromknown starting materials.

in an inert aqueous solvent. The particular acid used is The compoundsofformula (I) and (la) are useful benot Criti al and in rga acids Suchas hydrochloric cause they possess pharmacological activity in animals.acid. sulfuric acid and the like or organic acids such as I i lcompounds (I) d (l are usef l as trifluroacetic acid can be used. Thepreferred acids are h li id i agents i th treatment f li id i i theinorganic acids, especially hydrochloric acid. The particular,hyperlipoproteinemia, as indicated by the particular sol ent used andthe temperature and time fall in cholesterol levels in male albinoWistar rats condition for the reaction are not critical and are the i hi110 to 130 g, i i i ll Th rats are i same as in the preparation of thediastereoisomers salts r i d on drug-free laboratory h di f Seven dabove. The pro III) i recovered y nand then devided into groups of8 to10 animals. Each tional techniques, e.g., precipitation andrecrystalligroup, ith th ex e ti of the t l, i then i e zation. orally30 milligrams per kilogram of body weight per The compounds of formula(Villa) ar pr p r y diem of the compound for six days. At the end ofthis the following reaction scheme: period, the animals are anesthetizedwith sodium hexo- ME Hydrolysis (VIIIa) 5 YCH COOR a 2 I ca coorg N(III) (IX) om where barbital and bled from the carotid arteries. Serumor MH is an alkali metal hydride plasma samples are collected and 1.0ml. of serum is 5 is lower alkyl having 1 t0 4 Carbon atoms and added to9.0 ml, redistilled isopropanol. Two autoana- 1 and 2 are 85 Sat 011tlyzer cupsful of a mixture of zeolite-copper hydroxide The compounds orm are p p y and Lloydds reagent (Kersler, E., and Lederer, H. treatinga compound of o u II) with an alkali I965, Technicon Symposium, MadiadInc., New York, metal hydride followed by a halo-acetic acid ester in an345-347) are added, and the mixture is shaken for l inert solvent andhydrolyzing the ester (IX) obtained. hour. Cholesterol levels aredetermined using this sam- The haloacetic acid ester can be eitherbromoacetic ple by the standard Technicon N 24A (cholesterol) acid esteror chloroacetic acid ester, but the former is m h d l Th mean serum h ll levels are preferred. The alkali metal hydride is preferably sothencomputed and the hypocholesterolemic activity is dium hydride orpotassium hydride. The particular expressed as the fall in cholesterollevels as a percentinert solvent used is not critical butdimethylformamide age of the control level.

is particularly preferred. The temperature is not criti- For suchusages, compounds (I) and (la) may be adcal. but the process ispreferably carried out at a temministered orally or parenterally as suchor admixed perature of from about 0 to C, especially 20 to withconventional pharmaceutical carriers. They may 50C. The reaction can becarried out in one of the be administered orally in such forms astablets, dispersabove inert atmospheres, and the time may vary widelyible powders, granules, capsules, syrups and elixirs, and and is usuallyin the range of l to 24 hours. Recovery parenterally as solutions,suspensions, dispersions,

emulsions and the like, e.g., a sterile injectable aqueous suspension.These pharmaceutical preparations may contain up to. about 90 percent ofthe active ingredient in combination with the carrier or adjuvant.

dicated below which may be prepared by conventional techniques and areuseful as a hypocholesterolemic agent at a dose of one tablet or capsule2 to 4 times a day.

Furthermore, these compounds of formula (I) and (la) may be similarlyadministered in the form of their non-toxic pharmaceutically acceptableacid addition salts. Such salts possess the same order of activity asthe free base, are readily prepared by reacting the base with anappropriate acid and, accordingly, are included within the scope of theinvention. Representative of such salts are the mineral acid salts,suchas the hydrochloride, hydrobromide, sulfate, phosphate and the likeThe following pharmaceutical compositions are formulated with theindicated amount of active agent using ,conventionaltechniques. Theinjectable suspension and the oral liquid suspension represent formulaqtions useful as unit doses and may be administered as ahypocholesterolemic-agent. The injectable suspension is suitable foradministration once or twice a day whereas the oral liquid suspension issuitable administered 2, to 4 times per day for this purpose.

Ingredients l a-hydroxy-p-chlorophenethyl) i Weight (mg) sterileinjectable suspension oral liquid suspension-l-(p-chlorophenyl)-2.3-dihydroisoindole 200 200 sodium carboxy methylcellulose USP 1.25 12.5 methyl cellulose 0.4 v polyvinylpyrrolidone 5lecithin 3 benzyl alcohol 0.01 magnesium aluminum silicate 47.5 flavorq.s. color q.s.

' methyl paraben, USP 4.5 propyl paraben, USP 1.0 polysorbate 80 (e.gvTween 80) USP 5 sorbitol solution, 70% USP 2,500 buffer agent to adjustpH for desired stability q.s. q.s. water for injection, q.s. to '5 ml.

q.s. to 1 ml.

and the organic acids salts, such as the succinate, ben- EXAMPLE 1zoate, acetate, p-toluenesulfonate, benzene-sulfonate, maleate, malate,tartrate, methanesulfonate, cyclohexylsulfamate pyroglutamate and thelike.

The cholesterol reducing effective dosage of active ingredient employedin the treatment of lipidemia may vary depending on the particularcompound employed and the severity of the condition being treated.However, in general, satisfactory results are obtained when thecompounds (I) and (la) are administered at the daily dosage of fromabout 0.5 milligrams to about 100 milligrams per kilogram of animal bodyweight, preferably given in divided doses two to four times daily, or insustained release form. For most large mammals, the

total daily dosageis from about to about 1,500 milligrams. Dosage formssuitable for internal use comprise from about 7.5 to about 750milligrams of the,active compounds in intimate admixture with a solid orliquid pharmaceutically acceptable carrier or diluent.

The preferred pharmaceutical compositions fromthe standpoint ofpreparation and ease of administration are solid compositions,particularly hardfilled capsules and tablets containing from about 200to 500 milligrams of the active ingredient.

A representative formulation suitable for administra-- tion is a tabletor capsule containing the ingredientsinchlorophenyl)-3-ethoxy-lH-isoindole,

isoindole in 500 ml of absolute dimethylformamide is then addeddropwise. After completion of the addition,

the mixture is stirred at room temperature for 2 hours and 47.0 g. ofp-chlorophenacyl bromide in 500 ml of absolute dimethylformamide is thenadded dropwise. The mixture is stirred at room temperature overnight.The solvent is evaporated under reduced pressure andtheresidue-dissolved in methylene chloride and washed with water toyield l-(p-chlorophenacyl)-l-(pp 99lOl"C).

Following the above procedure but using an equivalent amount of a.phenacyl bromide; b. p-fluorophenacyl bromide; c. p-methoxyphenacylbromide;

d. o-trifluoromethylphenacyl bromide; ei m-trifluoromethylphenacylbromide; f. m-fluorophenacyl bromide:

g. o-fluorophenacyl bromide;

h. p-trifluoromethylphenacyl bromide; i. 3,4-dichlorophenyl bromide;

j. p-methylphenacyl bromide;

k. o-chlorophenacyl bromide or I. m-chlorophenacyl bromide in placeofthe p-chlorophenacyl bromide used therein, there is obtained:

a. l-phenacyl-l-(p-chlorophenyl)-3-ethoxy-1H- isoindole:

b. l-(p-fluorophenacyl)-l-(p-chlorophenyl)-3-ethoxylH-isoindole;

c. l-( p-methoxyphenacyl l -(p-chlorophenyl )-3- ethoxy-l H-isoindole;

d. l-(o-trifluoromethylphenacyl)-l-(p-chlorophenyl)-3'ethoxy-lH-isoindole;

e. l-(m-trifluoromethylphenacyl)-l-(p-chlorophenyl)-3-ethoxylH-isoindole;

f. l-(m-fluorophenacyl)-l-(pchlorophenyl)-3-ethoxy lH-isoindole;

g. l-(o-fluorophenacyl)-l-(p-chlorophenyl)-3-ethoxyl H-isoindole;

h. l-(p-trifluoromethylphenacyl)-l(pchlorophenyl)- 3-ethoxylH-isoindole;

l-(3.4-dichlorophenacyl)-l-(p-chlorphenyl)-3-ethoxylH-isoindole;

j. l-(p-methylphenacyl)-l-(p-chlorophenyl)-3-ethoxylH-isoindole;

k. l-(o-chlorophenacyl)-l-(p-chlorophenyl)-3-ethoxylHisoindole or l.l-(m-chlorophenacyl)-1-(p-chlorophenyl)-l-ethoxylH-isoindole,respectively.

l-( a-hydroxy-p-chlorophenethyl l -(p-chlorophenyl 2,3-dihydroisoindole.

To 22.5 g ofl-(p-chlorophenacyl)-l-(pchlorophenyl)-3-ethoxy-lH-isoindole dissolvedin 100 ml of anhydrous tetrahydrofuran and cooled with icebath is addeddropwise 100 ml ofa commercial solution of 1 molar diborane intetrahydrofuran. The solution is stirred for two hours at roomtemperature after which the solvent is evaporated under reducedpressure. Addition of 100 ml of water is followed by extraction withchloroform, to yieldl-(a-hydroxy-pchlorophenethyl)-l-(chlorophenyl)-2,3- dihydroisoindole.m.p.l57-l60C.

The l-( a-hydroxy-p-chlorophenethyl lpchlorophenyl)-2.3-dihydroisoindole of this example is an effectivehypocholesterolemic agent when administered orally at a dosage of 250milligrams twice a day.

Following the above procedure. but using an equivalent amount of a.l-phenacyll-(p-chlorphenyl)-3-ethoxy-1l-lisoindole:

b. l-(p-fluorophenacyl)-l-(p-chlorophenyl)-3-ethoxyll-l-isoindole;

c. l-( p-methoxyphenacyl l -(p-chlorophenyl)-3- ethoxyl H-isoindole;

d. l(o-trifluoromethylphenacyl)-1-(p-chlorophenyl)- 3-ethoxylH-isoindole;

e. l-(m-trifluoromethylphenacyl)-l-(p-chlorophenyl)- 3-ethoxylH-isoindole;

14 f. 1-(m-fluorophenacyl)-l-(p-chlorophenyl)-3-ethoxyl H-isoindole; g.l-(o-fluorophenacyl)-l-(pchlorophenyl)-3-ethoxyll-l-isoindole;

in place of thel-(p-chlorophenacyl)-l-(pchlorophenacyl)-3-ethoxy-lH-isoindole usedtherein there is obtained:

a. l-(a-hydroxyphenethyU- l-(p-chlorophenyl )-2,3-

dihydroisonidole (m.p. 139l40C);

. l-(a-hydroxyp-fluorophenethyl)-l-(pchlorophenyl)-2,3-dihydroisoindole(m.p. 154l55C);

.l-(a-hydroxy-p-methoxyphenethyl)-l-(pchlorophenyl)-2,3-dihydroisoindole(m.p.

l-( a-hydroxy-o-trifluoromethylphenethyl lpchlorophenyl)-2,3-dihydroisoindole;

e. 1-(a-hydroxy-m-trifluoromethylphenethyl l(pchlorophenyl)l2,3-dihydroisoindole;

. l(oz-hydroxy-m-fluorophenethyl l(-pchlorophenyl)-2,3-dihydroisoindole;

. l-( a-hydroxy-o-fluorophenethyl l-(pchlorophenyl)-2,3-dihydroisoindole;

h. l a-hydroxy-p-trifluoromethylphenethyl l-(pchlorophenyl)-2,3-dihydroisoindole;

. 1-( a-hydroxy-3,4-dichlorophenethyl l-(pchlorophenyl)2,3-dihydroisoindole; (m.p. l40-142C);

. l-( a-hydroxy-p-methylphenethyl l pchlorophenyl)-2,3-dihydroisoindolek. l-(01-hydroxy-o-chlorophenethyl 1 pchlorophenyl)-2,3-dihydroisoindoleor 1. 1-( a-hydroxy-m-chlorophenethyl lpchlorophenyl)-2,3-dihydroisoindole, respectively.

EXAMPLE 2 When essentially the same procedure as in example I is carriedout using an equivalent amount of l-phenyl- 3-ethoxy-1H-isoindole or1-(3,4-dichlorophenyl)-3- ethoxy-lH-isoindole in place of thel-(pchlorophenyl)-3-ethoxy-lH-isoindole used therein, there is obtainedafter treatment with sodium hydride and p-chlorophenacyl bromide,l-(p-ehlorophenacyl)- l-phenyl-3-ethoxyl H-isoindole orl-(pchlorophenacyl)-1-(3,4-dichlorophenyl)-3-ethoxy-1H- isoindolerespectively; and after treatment of these products with diborane, thereis obtained l-(ahydroxy-p-chlorophenethyl)-l-phenyl-2,3-dihydroisoindole or l-(a-hydroxy-p-chlorophenethyl)-l-(3,4-dichlorophenyl)-2,3-dihydroisoindole (m.p. l26C) respectively.

EXAMPLE 3 When the 1-(a-hydroxy-p-chlorophenethyl)-1-phenyl-2,3-dihydroisoindole of example 2 is dissolved in methanol andtreated with a methanolic solution of maleic acid. there is obtainedl-(oz-hydroxy-pchlorophenethyl)-l-phenyl-2,3-dihydroisoindole maleate(m.p. l5l-l53C).

Following essentially the above procedure, but using in place of thel-(a-hydroxy-p'chlorophenethyl)-lphenyl-Z,3-dihydroisoindole anequivalent amount of a. l-( a-hydroxy-o-trifluoromethylphenethyl l pchlorophenyl )-2,3-dihydroisoindole;

b. l-( oz-hydroxy-m-trifluoromethylphenethyl lpchlorophenyl)-2,3-dihydroisoindole;

chlorophenyl)-2,3-dihydroisoindole maleate (m.p. 162-l64C);

c. l-( oz-hydroxy-m-fluorophenethyl 1pchlorophenyl)-2,3-dihydroisoindole maleate (m.p. l92l94C);

d. l(a-hydroxy-o-fluorophenethyl l -(pchlorophenyl)-2,3-dihydroisoindolemaleate (m.p. l85l86C);

e. 1-( a-hydroxy-p-trifluoromethylphenethyl l-(pchlorophenyl)-2,3-dihyclroisoindole maleate (m.p. l78-180C);

f. l -(a-hydroxy-o-chlorophenethyl)-1-(pchlorophenyl)-2,3-dihydroisoindole maleate1-(a-hydroxy-m-chlorophenethyl)-l-(pchlorophenyl)-2,3-dihydroisoindolemaleate (l70-l72C), or

h. l-(oz-hydroxy-p-methylphenethyl l pchlorophenyl)-2,3-dihydroisoindole(m.p. 169 1 70C), respectively.

EXAMPLE 4 Step A:

l-(az-hydroxy-p-chlorophenethyl)- l -(p-chlorophenyl 3-ethoxylH-isoindole To 10.4 g ofl-(p-chlorophenacyl)-l-(pchlorophenyl)-3-ethoxy-lH-isoindole in 100 mlof absolute ethanol, 3.0 g of sodium borohydride are added. The mixtureis stirred at room temperature over night. The solvent is thenevaporated under reduced pressure. following which the residue isdissolved in methylene chloride, washed with water until neutral, anddried over potassium carbonate. The solvent is evaporated leaving 11.5 gof a solid (m.p. l-l23) which is chromatographed on silica gel to yieldtwo racemic isomers: Mixture A and Mixture B:

Mixture A: m.p. l44-l46 (6.3 g) and Mixture B: m.p. l36-138 (l.8 g)

Step B: 5 l-(a-hydroxy-p-chlorophenethyl)-l-(p-chlorophenyl)-2,3-dihydroisoindole.

In 20 ml of tetrahydrofuran, 2.1 g of l-(a-hydroxy-pchlorophenethyl l-(p-chlor0phenyl )-3-ethoxyl H- isoindole, (Mixture A: m.p. l44l46) isreduced with 6 ml of commercial diborane in tetrahydrofuran solution atroom temperature over night. Initial work-up yields the title product;m.p. 159-162C (m.p. of the maleic acid addition salt l91l92C).

When the same reduction is carried out with Mixture B of Step A (m.p.l36l38C), the corresponding product is isolated as the maleic acidaddition salt. m.p. l l9-l2lC. This product is inactive.

2O EXAMPLE 5 Step A: 3-(a-hydroxy-p-chlorophenethyl)-3-(p-chlorophenyl)-phthalimidine 2 One gram of1(a-hydroxy-pchlorophenethyl)-1-(pchlorophenyl)-3-ethoxy-lH-isoindole(Mixture A, Step A of example 4), is heated in ml of 95% ethanol and 1ml of 2N hydrochloric acid at 55-60C for 90 minutes. After evaporationof the solvent, the residue is filtered and washed with water andrecrystallized from methylene chloride/hexane to yield the title racemicisomer A: mp. 21 l2l2.

Step B: 1-( 04-hydroxy-p-chlorophenethyl 1 p-chlorophenyl2,3-dihydroisoindole.

When the product from Mixture A of Step A of this example is treatedwith diborane in accordance with the process of Step B of example 4,there is again obtained l-( oz-hydroxy-p-chlorophenethyl lpchlorophenyl)-2,3-dihydroisoindole (m.p. 159-l62C).

EXAMPLE 6 Step A: 3-( pchlorophenacyl )-3-(p-chlorophenyl phthalimidine.

When the acid hydrolysis procedure of Step A of example 5 is carried outusing l-(p-chlorophenacyl-l-(pchlorophenyl)-3-ethoxy-lH-isoindole ofexample 1, there is obtained3-(p-chlorophenacyl)-3-(pchlorophenyl)-phthalimidine (m.p. l92l94C).

Step B: 3-( a-hydroxy-p-chlorophenethyl )-3-( p-chlorophenylphthalimidine.

When the product of Step A is treated with sodium borohydride using theprocess of Step A of Example 4, there is obtained after chromatography3-(a-hydroxyp-chlorophenethyl)-3-(p-chlorophenyl)-phthalimidine (m.p. 2ll2l2C).

Step C: l-( a-hydroxy-p-chlorophenethyl l p-chlorophenyl2,3-dihydroisoindole.

When the product of Step B of this example is treated with diboraneusing the process of Step B of example 4, there is obtainedl-(a-hydroxy-p-chlorophenethyl)- l-(p-chlorophenyl)-2.3-dihydroisoindole(m.p. l59l6lC) EXAMPLE 7 l-( a-hydroxy-p-chlorophenethyl lp-chlorophenyl 2.3-dihydroisoindole.

When the product of Step A from example 6 is treated with dibroane usingthe process of Step B of example 4. there is obtainedl-(a-hydroxy-pchlorophenethyl)-l-(p-chlorophenyl) 2,3- dihydroisoindole.

EXAMPLE 8 Step A: l-(p-chlorophenyl)-3-oxo-isoindoline acetic acid.

Into a flask equipped with a mechanical stirrer, condenser and droppingfunnel is charged under nitrogen 13 grams of sodium hydride in 250 ml.of anhydrous dimethyl formamide. To this. 136 grams ofl-(pchlorophenyl)-3-ethoxy-lH-isoindole in 500 ml of absolute DMF isadded dropwise. After completion of the addition, the mixture is stirredat room temperature for 2 hours following which 77.5 grams ofmethylbromoacetate is added dropwise. After standing at room temperatureover night, the solvent is evaporated under reduced pressure and theresidue is dissolved in methylene chloride. This solution is washed withwater and after separation, the organic phase is dissolved in 850 ml ofmethanol and warmed on the water bath 2 hours with 750 ml of 2Nhydrochloric acid. The solvent is evaporated under reduced pressure andthe residue is dissolved in 2N sodium hydroxide. After extracting withether. a recemic mixture of the and isomers ofl-(p-chlorophenyl)-3-oxo-isoindoline-acetic acid is precipitated fromthe aqueous layer by the addition of 2N hydrochloric acid (m.p.234-236).

To 222 grams of the racemic mixture prepared as above in 2,500 ml ofmethanol is added 295.0 grams of brucine in 800 ml. of methanol. Fromthe solution, 260 g. of a solid complex precipitates which is filteredoff, suspended in 500 ml. of methanol and acidified with 160 ml of 2Nhydrochloric acid. On cooling, the acid crystallizes out, is filteredand then recrystallized from methanol with a melting point of 2162l7 andan optical rotation of a =+253. (The optical rotations in this exampleare measured at a concentration of lOmg/ml in ethanol at 23C using thesodium D-line).

The solution containing the acid complexed with brucine is evaporated toan oil, which is dissolved in methanol and treated with 2N hydrochloricacid. The solid is filtered off and recrystallized from methanol (mp.2l52l6; a,,=-244).

Following essentially the above procedure. but using an equivalentamount of l-phenyl-3-ethoxy-1H- isoindole orl-(3.4-dichlorophenyl)-3-ethoxy-lH- isoindole in place of the1-(p-chlorophenyl)-3-ethoxylH-isoindole used therein, there is obtainedthe and isomers of l-phenyl-3-oxo-isoindoline-acetic acid orl-(3,4-dichlorophenyl)-3-oxo-isoindolineacetic acid respectively.

Step B: (+)-3-( p-chlorophenacyl )-3-( p-chlorophenyl phthalimidine.

Thirty grams of the acid above is treated with 60 ml. of thionylchlorideunder nitrogen in 300 ml. of dichloroethane and drops ofdimethylformamide. The

mixture is refluxed for 30 minutes at 50 to 60 and the solvent isevaporated under reduced pressure. The crude acid chloride,(+)-l-(pchlorophenyl)-3-oxoisoindoline acetic acid chloride, isdissolved in ml of dichloroethane and to this solution is added 48 gm.of chlorobenzene. The mixture is cooled to 50 and 26 grams of aluminuimchloride is added in small portions. After 2 hours. the mixture isallowed to warm to room temperature. The reactants are then poured onice, extracted with methylene chloride. washed with sodium carbonatesolution, dried and evaporated. The crude material (58 g) is dissolvedin methylene chloride and ether is added to form a cloudy mixture. Aseed crystal is added to crystallize the(+)-3-(pchlorophenacyl)-3-(p-chlorophenyl)phthalimidine, (mp. l7l-l72;a,,=+332).

The ()-3-(p-chlorophenacyl)-3-(p-chlorophenyl)- phthalimidine (mp. l72;a,,33l) is obtained following the above procedure and chromatographingon silica; but using an equivalent amount of()-3-(pchlorophenyl)-3-oxo-isoindoline-acetic acid in place of the(+)-l-(p-chlorophenyl)-3-oxo-isoindoline acetic acid to prepare the()-l-(p-chlorophenyl)-3-oxoisoindoline acetic acid chloride.

Following the above procedure but using an equivalent amount of a.benzene; fluorobenzene;

c. methoxybenzene;

d. trifluoromethylbenzene; e. 3,4-dichlorobenzene or; f. toluene inplace of the chlorobenzene used therein, there is obtained the andisomers of a. 3-phenacyl 3(p-chlorophenyl)-phthalimidine;

3-(p-fluorophenacyl)-3-(p-chlorophenyl)- phthalimidine;

. 3-(p-methoxyphenacyl)-3-(p-chlorophenyl)- phthalimidine;

d. 3-(p-trifluoromethylphenacyl)-3-(p-chlorophenyl)- phthalimidine;

e. 3(3,4-dichlorophenacyl)-3-(p-chlorophenyl)- phthalimidine or f.3-(p-methylphenacyl)-3-(p-chlorophenyl)- phthalimidine respectively.

When the (+)-l-(p-chlorophenyl)-3-oxo-isoindolineacetic acid of thisexample is replaced by an equivalent amount of the or isomer ofl-phenyl-3-0xoisoindoline-acetic acid or l-(3,4-dichlorophenyl)-3-oxo-isoindoline-acetic acid there is obtained the corresponding orisomers of l-phenyl-3-oxo isoindoline-acetic acid chloride orl-(3,4-dichlorophenyl)-3- oxo-isoindoline-acetic acid chloride beforetreatment with the chlorobenzene and the corresponding or isomer of3-phenyl-3-(p-chlorophenacyl)- phthalimidine or3-(3,4-dichloropheriyl)-3-(pchlorophenacyl)-phthalimidine respectivelyafter treatment with chlorobenzene.

Step C:(+)-3-(a-hydroxy-p-chlorophenethyl)-3-(pchlorophenyl)-phthalimidine To25 g. of (+)-3-(p-chlorophenacyl)-3-(pchlorophenyl)-phthalimidine in 500ml. of absolute ethanol under nitrogen and cooled in an ice bath, 3.0

g. of sodium borohydride are added. The mixture is stirred at roomtemperature for 2 hours. The solvent is then evaporated under reducedpressure, following which the residue is dissolved in methylenechloride, washed with water until neutral, and dried over potassiumcarbonate. The solvent is evaporated leaving 32 g. of crude productwhich is chromatographed on silica gel first with benzene then withincreasingly stronger chloroform in benzene solution to yield the titleproduct (23l-233; a,,=+l82) Continue elution with chloroform yields asecond isomer (a,,=+79).

Following the above procedure and using()-3-(pchlorophenacyl)-3-(p-chlorophenyl)-phthalimidine in place of the(+)isomer, there is obtained()-3-(ahydroxy-p-chlorophenethyl)-3-(p-chlorophenyl)- phthalimidine(m.p. 23l-233; a,,=-l84).

Again continued elution with chloroform yields a second isomer(a,,=-79).

Step D: l -(a-hydroxy-p-chlorophenethyl l pchlorophenyl)-2,3-dihydroisoindole.

In 100 ml. of dry tetrahydrofuran, 4.5 g. of()-3-(ahydroxy-p-chlorophenethyl)-3-(p'chlorophenyl)-3-phthalimidine(a,,==l84), is cooled with ice and reduced with 30 ml of 1molar commercial diborane in tetrahydrofuran solution. The mixture isleft at 7C for 2 days following which the solvent is evaporated and theproduct dissolved in methylene chloride. After washing with potassiumcarbonate and water and drying over potassium carbonate,chromatographing as above with benzene and chloroform yields the titleproduct (a,,=7l).

The l a-hydroxy-p-chlorophenethyl l pchlorophenyl)-2,3-dihydroisoindoleof this example is an effective hypocholesterolemic agent whenadministered orally at a dosage of 250 milligrams twice a day.

When the same reduction is carried out with the isomer of Step A, thecorresponding l -(a-hydroxyp-chlorophenethyl)-l-(p-chlorophenyl)-2,3-dihydroisoindole (a, -l-65) is obtained.

When the above process is carried out with isomer (z=+79) and isomer(a=79), the products obtained are inactive isomers (a=60) and (0z=+59)respectively which are pharmaceutically inactive.

Following the above procedures, but using an equivalent amount of eitherthe or isomer of a. 3-phenacyl-3-(p-chlorophenyl)-phthalimidine;

b. 3-(p-fluorophenacyl)-3-(p-chlorophenyl)- phthalimidine;

. 3-(p-methoxyphenacyl)-3-(p-chlorophenyl)- phthalimidine;

d. 3-(p-trifluoromethylphenacyl)-3-(p-chlorophenyl)- phthalimidine;

e. 3-(3,4-dichlorophenacyl)-3-(pchlorophenyl)- phthalimidine;

f. 3-(p-methylphenacyl)-3-(p-chlorophenyl)- phthalimidine;

g. 3-phenyl-3-(p-chlorophenacyl) phthalimidine or h.3-(3,4-dichlorophenyl)-3-(p-chlorophenacyl)- phthalimidine,

in place of the (+)-3-(p-chlorophenacyl)-3-(pchlorophenyl)-phthalimidineused therein there is obtained after carrying out the process of Step C,the corresponding or isomers of respectively, and the corresponding orisomers of a. l-(a-hydroxyphenethyl 1 p-chlorophenyl )-2,3-

dihydroisoindole; 1-( a-hydroxy-p-fluorophenethyl- 1-(pchlorophenyl)-2,3-dihydroisoindole; 1-( a-hydroxy-p-methoxyphenethyll pchlorophenyl )-2,3-dihydroisoindole d. l-(oz-hydroxy-p-trifluoromethylphenethyl)- l -(pchlorophenyl)-2,3-dihydroisoindole; e. l-( a-hydroxy-3,4-dichlorophenetnyl)-1-(pchlorophenyl )-2,3-dihydroisoindole; f. l-(a-hydroxy-p-methylphenethyl 1 pchlorophenyl)-2,3-dihydroisoindole; g.l-( a-hydroxy-p-chlorophenethyl l -phenyl-2,3-

dihydroisoindole or l-(a-hydroxy-p-chlorophenethyl)-1-(3,4-

dichlorophenyl )-2,3-dihydroisoindole,

respectively after carrying out the process of Step D.

EXAMPLE 9 ()-1-(a-hydroxy-p-chlorophenethyl)-l-(pchlorophenyl)-2,3-dihydroisoindole To a suspension of 48.0 grams (0.125 mol) ofracemic 1-(a-hydroxy-p-chlorophenethyl 1pchlorophenyl)-2,3-dihydroisoindole from example 1 in 700 ml. ofmethanol there is added 19.] g of D-(+)- pyroglutamic acid(D-(+)-2-pyrrolidone-5-carboxylic acid) of an estimated optical purityof percent. The solution is filtered and the product()-l-(oz-hydroxyp-chlorophenethyl)-l-(p chlorophenyl) 2,3-

dihydroisoindole-D-(+)-pyroglutamate is precipitated by the addition ofether. The product is filtered off and dried (m.p. l80-l 8 1; a,,=5.24;yield 28.0 g, 87 percent).

The free base is liberated by treating a methanol solution of the abovesalt with 2N sodium hyroxide and extracting with methylene chloride. Theproduct is isolated as an amorphous foam (a,,=-70.25)

To 5.2 grams of the above free base in 5 ml. of methanol, 2.2 g. ofpercent'phosphoric acid is added following which ether is added toprecipitate the phosphate salt of the title compound (m.p. l07-109;a,,=+27.5; yield 7.0 g).

The filtrate remaining above after the separation of the pyroglutamateof the title product is evaporated to dryness to precipitate loz-hydroxy-pchlorophenethyl)-1-(p-chlorophenyl)-2,3- dihydroisoindoleD-(+)-pyroglutamate. I

When the above salt in methanol is treated with 2N NaOH and extractedwith methylene chloride. the free base l a-hydroxy-p-chlorophenethyl lpchlorophenyl)-2.3-dihydroisoindole is obtained as a foam. Treatmentwith L-()-pyroglutamic acid yields the salt (a,,=+5.24) which ontreatment with 2N NaOH again yields the pure(+)-l-(a-hydroxypchlorophenethyl l p-chlorophenyl )-2,3-dihydroisoindole (a,,=+70.25; phosphate a,,=-27.5)

When the above process is carried out using an equivalent amount of aracemic mixture of l-(ahydroxy-3.4-dichlorophenethyU-l-(p-chlorophenyl)-2,3-dihydroisoindole prepared as in example 1 in place of the racemicmixture of l-(a-hydroxy-pchlorophenethyU-l-(p-chlorophenyl)-2,3-dihydroisoindole there is obtained ()-l-(a-hydroxy-3.4-dichlorophenyU-l-(p-chlorophenyl)-2,3- dihydroisoindole (a,,=64.96;D'pyroglutamic acid salt m.p. l65-l68C.; u -6.96) and(+)-l-(ahydroxy34-dichlorophenethyl)-l-(pchlorophenyl)-2.3-dihydroisoindole (a,,=+62.5).

What is claimed is:

l. A compound of the formula:

salt

where R and R each independently represent hydrogen or halo having anatomic weight of l9 to 36 and R and R each independently representshydrogen,

lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4carbon atoms, halo having an atomic weight of 19 to 36 ortrifluoromethyl provided that when both R and R are trifluoromethyl,they are not on adjacent carbon atoms; or a pharmaceutically acceptableacid addition salt thereof.

2. The compound of claim 1 which isl-(a-hydroxyp-chlorophenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindole.

3. The compound of claim 1 which ishydroxyphenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindole.

4. The compound of claim 1 which is l(ahydroxyp-fiuorophenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindolet 5. Thecompound of claim 1 which isl-(a-hydroxyp-methoxyphenethyl)-l-(p-chlorophenyl)-2,3-dihydroisoindole.

6. The compound of claim 1 which isl'(a-hydroxyo-trifluoromethylphenethyl)-l-(p-chlorophenyl)2,3-dihydroisoindole.

7. The compound of claim 1 which isl-(a-hydroxym-trifluoromethylphenethyl l p-chlorophenyl )-2,3-dihydroisoindole.

8. The compound of claim 1 which isl-(a-hydroxym-fluorophenethyl)-l-(p-chlorophenyl)2,3- dihydroisoindole.

9. The compound of claim 1 which isl-(a-hydroxyo-fluorophenethyll-l-(p-chlorophenyl)-2,3- dihydroisoindole.

10. The compound of claim 1 which isl-(a-hydroxyp-trifluoromethylphenethyl)-l-(p-chlorophenyl)-2,3-dihydroisoindole.

11. The compound of claim 1 which is l-(a-hydroxy-3,4-dichlorophenethyl)-l-(p-chlorophenyl)-2,3- dihydroisoindole.

12. The compound of claim 1 which is l-(a-hydroxyp-chlorophenethyl lphenyl-Z,3-dihydroisoindole.

13. The compound of claim 1 which isl-(a-hydroxyp-chlorophenethyl)-l-(3,4-dichlorophenyl)-2,3-dihydroisoindole.

14. The compound of claim 1 which is l-(a-hydroxyo-chlorophenethyll-(p-chlorophenyl )-2,3- dihydroisoindole.

15. The compound of claim 1 which is l-(a-hydroxym-chlorophenethyl lp-chlorophenyl )-2,3- dihydroisoindole.

16. The compound of claim 1 which is l-(a-hydroxyp-methylphenethyl lp-chlorophenyl )-2 ,3- dihydroisoindole.

17. A pharmaceutically active compound of the formula with diborane inan inert solvent where X is CO or CHOH; Z is CO or A is hydrogen orwhich comprises treating a compound of the formula AB together representa carbon to nitrogen double bond when Z is l -(!JOC h5 3 and R R R R andthe proviso are as set out in claim l. The Process according to Claim 20in which X is with an alkali metal hydride reducing agent in an inert Zsolvent, where Z, R R R R and the proviso are as set out in i claim 20.25. A compound of formula and AB represents a carbon to nitrogen doublebond.

22. A compound of the formula R 1-1 lca N OH R R Z A where CH Z, R R R Rand the proviso are as set out in 2 claim 23. 26. A process forpreparing a compound of the for- Z A mula R where X, Z, R, R R R and theproviso are as set out in claim 20.

2 23. A compound of the formula 3 R NH h R R CH C which compriseshydrolyzing a compound of the formula N O R where 2 R R R R and theproviso are as set out in claim 24. A process for preparing a compoundof the formula v 1 N R 2 CH in an inert solvent under acid conditions ata pH below 3, where ,i H Rh 2 A X, R R R R and the proviso are as setout in claim 22.

27. A compound of the formula which comprises treating a compound of theformula CH X i h NH where X. R,R R R and the proviso are as set out inclaim 25, with an alkali metal reducing agent in an inert solvent,

28. A process for preparing the compounds of claim Where 17 whichcomprises reducing a compound of the for- 1 2- 3 4 and the Proviso areas Set out in Claim mula: 2 28 to obtain a product of the formula:

. I g i g Sell/em Where t I and separating the product into itscomponent isomers.

1,7 4 n e proviso are as se out in c aim A compound of the formula 29. Acompound of the formula: R

CH -C R OH O 0 where R R R R and the proviso' are as set out in claimwhere Rh R), R3, R4 and the proviso are as Set out in claim 32. Aprocess for preparing a compound of the formula 30. A process forpreparing a compound of the'formula l R l- 3 --C CH CH A o R NH H h 27which comprises treating a compound of the formula h -COOB with ahalogenating agent to form an intermediate of the formula CH COY andthereafter treating said intermediate with a compound of the formula inan inert solvent in the presence of a Friedel Craft catalyst where Y ishalo having an atomic weight of about 35 to 80 where Y, R,, R and theproviso are set out in claim 31.

34. A compound of the formula where R R and the proviso are as set outin claim 31. 35. A process for preparing enantiomers of claim 17, whichcomprises reducing a compound of the formula:

with diborane in an inert solvent to form ture of the formula:

E f/{ l a racemic mixcH -cH 6 OH 4 where R R R and R are as set out inclaim 17, reacting said racemic mixture with D-(+)- pyroglutamic acid,separating the resulting diastereoisomers by crystallization andliberating'the enantiomers from the diastereoisomers by treatment with abase.

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 which is 1-( Alpha -hydroxy-p-chlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 3. The compound of claim 1 which is 1-( Alpha -hydroxyphenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 4. The compound of claim 1 which is 1-( Alpha -hydroxy-p-fluorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 5. The compound of claim 1 which is 1-( Alpha -hydroxy-p-methoxyphenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 6. The compound of claim 1 which is 1-( Alpha -hydroxy-o-trifluoromethylphenethyl)-1-(p-chlorophenyl)-2,3 -dihydroisoindole.
 7. The compound of claim 1 which is 1-( Alpha -hydroxy-m-trifluoromethylphenethyl)-1-(p-chlorophenyl)-2,3 -dihydroisoindole.
 8. The compound of claim 1 which is 1-( Alpha -hydroxy-m-fluorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 9. The compound of claim 1 which is 1-( Alpha -hydroxy-o-fluorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 10. The compound of claim 1 which is 1-( Alpha -hydroxy-p-trifluoromethylphenethyl)-1-(p-chlorophenyl)-2,3 -dihydroisoindole.
 11. The compound of claim 1 which is 1-( Alpha -hydroxy-3,4-dichlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 12. The compound of claim 1 which is 1-( Alpha -hydroxy-p-chlorophenethyl)-1-phenyl-2,3-dihydroisoindole.
 13. The compound of claim 1 which is 1-( Alpha -hydroxy-p-chlorophenethyl)-1-(3,4-dichlorophenyl)-2,3-dihydroisoindole.
 14. The compound of claim 1 which is 1-( Alpha -hydroxy-o-chlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 15. The compound of claim 1 which is 1-( Alpha -hydroxy-m-chlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 16. The compound of claim 1 which is 1-( Alpha -hydroxy-p-methylphenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 17. A pharmaceutically active compound of the formula
 18. The compound of claim 17 which is (+)-1-( Alpha -hydroxy-p-chlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 19. The compound of claim 17 which is (-)-1-( Alpha -hydroxy-p-chlorophenethyl)-1-(p-chlorophenyl)-2,3-dihydroisoindole.
 20. A process for preparing the compounds of claim 1 which comprises reducing a compound of the formula:
 21. The process according to claim 20 in which X is -Co-, Z is
 22. A compound of the formula
 23. A compound of the formula
 24. A process for prepaRing a compound of the formula
 25. A compound of formula
 26. A process for preparing a compound of the formula
 27. A compound of the formula
 28. A process for preparing the compounds of claim 17 which comprises reducing a compound of the formula:
 29. A compound of the formula:
 30. A process for preparing a compound of the formula
 31. A compound of the formula
 32. A process for preparing a compound of the formula
 33. A compound of the formula
 34. A compound of the formula
 35. A process for preparing enantiomers of claim 17, which comprises reducing a compound of the formula: 